Autoimmune disorders are diseases caused by the body producing an inappropriate immune response against its own tissues, in which the immune system creates T lymphocytes and autoantibodies that attack one's own cells, tissues, and/or organs. Researchers have identified 80-100 different autoimmune diseases and suspect at least 40 additional diseases have an autoimmune basis.
Autoimmune disorders are classified into two types, organ-specific (directed mainly at one organ) and non-organ-specific (widely spread throughout the body). Examples of organ-specific autoimmune disorders are insulin-dependent Type 1 diabetes, which affects the pancreas, Hashimoto's thyroiditis and Graves' disease, which affects the thyroid gland, pernicious anemia, which affects the stomach, Addison's disease, which affects the adrenal glands, chronic active hepatitis, which affects the liver and myasthenia gravis which, affects the muscles. Examples of non-organ-specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis and lupus.
Autoimmune diseases are often chronic, debilitating and life-threatening. The National Institutes of Health (NIH) estimates up to 23.5 million Americans suffer from autoimmune disease and that the prevalence is rising. It has been estimated that autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65 years. Most autoimmune diseases cannot yet be treated directly, but are treated to alleviate the symptoms associated with the condition. Some of the current treatments include administration of corticosteroid drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or more powerful immunosuppressant drugs such as cyclophosphamide, methotrexate and azathioprine that suppress the immune response and stop the progression of the disease. Radiation of the lymph nodes and plasmapheresis (a procedure that removes the diseased cells and harmful molecules from the blood circulation) are other ways of treating an autoimmune disease. However, these treatments often have devastating long-term side effects.
One of the most prevalent organ-specific autoimmune diseases, Type 1 diabetes, is characterized by the production of autoantibodies that target the insulin-secreting pancreatic beta cells. The destruction of the beta cells is mainly due to the action of T cells. In most cases, T cells can respond to an antigen only when the antigen is properly presented by an antigen presenting cell expressing the appropriate major histocompatibility complex (MHC) molecule. Thus, T cell immune response to an antigen requires recognition by the T cell receptor of an antigen coupled to a MHC molecule, and this recognition requires the assembly of a tri-molecular complex between an antigen, a MHC molecule and T cell receptor. In particular, the recognized peptide (when peptide autoantigen) must be in an appropriate register (or position along the MHC peptide binding groove).
Evidence strongly indicates that insulin/proinsulin is a key or primary auto-antigen in the development of type 1 diabetes in the NOD (non-obese diabetic) mouse model. Initial cloning of T cells from islets of NOD mice led to the discovery that the native insulin B chain amino acids 9-23 (B:9-23 insulin peptide) is the dominant antigenic peptide epitope presented by the class II MHC molecule I-A. Mice lacking the native B:9-23 sequence fail to develop diabetes and development of insulin autoantibodies and insulitis are markedly decreased. Restoring the native B:9-23 sequence with an islet transplant (but not bone marrow transplant) or peptide immunization, or a native proinsulin transgene, restores anti-insulin autoimmunity and generates CD4 T cells that cause diabetes.
The major genetic determinant of islet autoimmunity and diabetes in man and animal models are genes within the major histocompatibility complex, and in particular, class II MHC alleles. The NOD mice's unique sequence of IA (homologous to DQ of man) and lack of expression of I-E (shared with many standard mouse strains) are essential for the development of diabetes. The crystal structure of I-Ag7 with bound peptides has allowed the modeling of peptide binding to this molecule. Similar modeling has been performed for the human diabetogenic allele/molecule DQ8, which has analogous sequence to I-Ag7. Unanue and coworkers have defined two different registers of binding of the B:9-23 peptide to I-Ag7 and multiple investigators have utilized the B:9-23 peptide for prevention of diabetes (Levisetti M G, Suri A, Petzold S J, and Unanue E R, J. Immunol. 178(10):6051-6057 (2007); Bresson DL von Herrath M, Autoimmun. Rev. 6(5):315-322 (2007); Fukushima K, Abiru N, Nagayama Y et. al., Biochem. Biophys. Res. Com. 367(4):719-724, 2008).
There are alternative hypotheses as to why I-Ag7 (and DQB1*0302 44) is associated with islet autoimmunity. One hypothesis is that the molecule is a poor binder of peptides and potentially unstable, and such instability or defective binding might limit negative selection of autoimmune T cells within the thymus. Another hypothesis is that I-Ag7 is critical for presentation of specific autoantigenic peptide(s) in the periphery. The second hypothesis is supported by the observation that I-A alleles such as IAk prevent NOD diabetes but enhance alternative autoimmune disorders, suggesting that class II alleles determine the specific organ targeted rather than general susceptibility to autoimmunity.
Thus, there exists a need in the art for safer and more effective methods for treatment and prevention of autoimmune diseases. The instant invention addresses these needs by providing small molecules useful in the treatment and prevention of autoimmune diseases.